Immunotherapy refers to modulating a person's immune responses to impart a desirable therapeutic effect. Immunotherapeutics refer to those compositions which, when administered to an individual, modulate the individual's immune system sufficient to ultimately decrease symptoms which are associated with undesirable immune responses or to ultimately alleviate symptoms by increasing desirable immune responses. In some cases, immunotherapy is part of a vaccination protocol in which the individual is administered a vaccine that exposes the individual to an immunogen against which the individual generates an immune response in such cases, the immunotherapeutic increases the immune response and/or selectively enhances a portion of the immune response (such as the cellular arm or the humoral arm) which is desirable to treat or prevent the particular condition, infection or disease.
Vaccine protocols can be improved by the delivery of agents that modulate a person's immune responses to induce an improved immune response. In some vaccination protocols in which the individual is administered a vaccine that exposes the individual to an immunogen against which the individual generates an immune response, an agent is provided that increases the immune response and/or selectively enhances a portion of the immune response (such as the cellular arm or the humoral arm) which is desirable to treat or prevent the particular condition, infection or disease.
Vaccines are useful to immunize individuals against target antigens such as allergens, pathogen antigens or antigens associated with cells involved in human diseases. Antigens associated with cells involved in human diseases include cancer-associated tumor antigens and antigens associated with cells involved in autoimmune diseases.
In designing such vaccines, it has been recognized that vaccines that produce the target antigen in cells of the vaccinated individual are effective in inducing the cellular arm of the immune system. Specifically, live attenuated vaccines, recombinant vaccines which use avirulent vectors, and DNA vaccines each lead to the production of antigens in the cell of the vaccinated individual which results in induction of the cellular arm of the immune system. On the other hand, killed or inactivated vaccines, and sub-unit vaccines which comprise only proteins do not induce good cellular immune responses although they do induce an effective humoral response.
A cellular immune response is often necessary to provide protection against pathogen infection and to provide effective immune-mediated therapy for treatment of pathogen infection, cancer or autoimmune diseases. Accordingly, vaccines that produce the target antigen in cells of the vaccinated individual such as live attenuated vaccines, recombinant vaccines that use avirulent vectors and DNA vaccines are often preferred.
Chikungunya virus (CHIKV) is an alphavirus indigenous to tropical Africa and Asia, where it is transmitted to humans by the bite of infected mosquitoes, usually of the genus Aedes [1]. Chikungunya fever, the disease caused by CHIKV, was first recognized in epidemic form in East Africa during 1952-1953 [2]. Infection of humans by CHIKV can cause a syndrome characterized by fever, headache, rash, malaise, nausea, vomiting, myalgia, severe arthralgia and occasionally neurological manifestations such as acute limb weakness. It is also associated with a fatal haemorrhagic condition. Other symptoms include muscle aches and retro-orbital pains. Chikungunya disease is rarely fatal but is associated with significant morbidity. Chikungunya illness has an approximate incubation period of 1-2 weeks. The word “chikungunya” is thought to derive from description in local dialect of the contorted posture of patients afflicted with the severe joint pain associated with this disease [1-3].
Because Chikungunya has epidemic potential that can produce a sudden debilitating disease, it is a potential threat to the developing world, the developed world based on its continued spread and as military threat due to soldier deployment in newly emerging endemic region conflict zones is considerable. CHIKV infections have a significant impact economically as, local businesses are affected by absenteeism in endemic areas due to the incapacitating symptoms of this infection on employees. This economic effect is highest on the individual family members who are unable to work for weeks or months. Due to the debilitating infection sequelai, the lack of specific antiviral treatment and any current usable vaccine to prevent the disease is a major impediment to managing or controlling new CHIKV outbreaks.
CHIKV is spread by the bite of an infected mosquito. Mosquitoes become infected when they feed on CHIKV infected individuals. Monkeys, and possibly other wild animals, may also get infected but their role as reservoirs of the CHIKV is not yet documented. Infected mosquitoes can then spread the virus to other humans when they bite. Aedes aegypti (the yellow fever mosquito), a household container breeder and aggressive daytime biter which is attracted to humans, is the primary vector of CHIKV to humans. Aedes albopictus (the Asian tiger mosquito) may also play a role in human transmission is Asia, and various forest-dwelling mosquito species in Africa have been found to be infected with the virus [11-17]. Because CHIK fever epidemics are sustained by human-mosquito-human transmission, the epidemic cycle is similar to those of dengue and urban yellow fever. Large outbreaks of CHIK fever have been reported recently on several islands in the Indian Ocean and in India [4-7].
Since late 2004, the Chikungunya virus has reemerged with large outbreaks in various parts of the world predominantly in the Indian Ocean islands. At the beginning of 2006, after a period of lower transmission during the winter and with the arrival of the Southern Hemisphere summer, Reunion Island suffered an explosive outbreak. An estimate of 266,000 residents (population 770,000) infected with CHIKV was reported, and 248 death certificates gave CHIKV as the possible cause of death [10,12]. Evidence for intrauterine infection in pregnant women and vertical transmission has been documented [12, 13, 17]. Sequence analysis has revealed the existence of geographically clustered lineages of the virus. Phylogenetic analyses based on partial E1 sequences revealed the existence of three distinct phylogroups for CHIKV: one with the West African isolates, another including the Asian isolates and one regrouping the Eastern, Central and South African isolates [15,17].
In 2006, CHIK fever cases also have been reported in travelers returning from known outbreak areas to Europe, Canada, the Caribbean (Martinique), and South America (French Guyana) [5-9]. During 2005-2006, 12 cases of CHIK fever were diagnosed serologically and virologically at CDC (USA) in travelers who arrived in the United States from areas known to be epidemic or endemic for CHIK fever [10].
These infections have caused public health crises and grabbed the attention of the researchers worldwide. Importantly, most Chikungunya virus infections completely resolve within weeks or months. There have been, however, documented cases of CHIKV-induced arthralgia persisting for several years developing chronic joint problems. The fact that infection resolves after a long period supports that the immune system can rally to control this infection eventually. Furthermore, such a clearance phenotype supports a role in clearance for the T cell response. Earlier attempts to develop vaccines against Chikungunya such as formalin killed vaccine, Tween ether inactivated virus vaccine and live attenuated vaccines were moderately successful however, they were discontinued for various reasons [3]. Moreover all these vaccines were reported to produce only a serological response without induction of useful cellular immunity.
The frequency of recent epidemics in the Indian Ocean and La Reunion islands suggests that a new vector perhaps is carrying the virus, as Aedes aegypti are not found there. In fact, a relative the Asian tiger mosquito, Aedes albopictus, may be the culprit which and has raised concerns in the world health community regarding the potential for a CHIK virus pandemic.
Accordingly steps should be taken to develop methods for control of CHIKV. Unfortunately, currently is no specific treatment for Chikungunya virus and there is no vaccine currently available. Recently studies have demonstrated that an envelope E1-A226V mutation is directly responsible for a significant increase in CHIKV infectivity for Aedes albopictus, and further confirmed that a single amino acid substitution can influence vector specificity. This finding provides a plausible explanation of how this mutant virus caused an epidemic in a region lacking the typical insect vector [18]. There is no specific vaccine or specific antiviral treatment for Chikungunya. Live attenuated vaccine trials were carried out in 2000, but funding for the project was discontinued and there is no vaccine currently available. However, several adverse events associated with this prior vaccine are well documented, accordingly, new vaccine strategies must be developed [3,5].
The sheer magnitude of the 2005-2007, Chikungunya outbreaks underscores the need for a safe and effective vaccine against CHIKV [6]. There remains a need for a vaccine which can prevent individuals from becoming infected with CHIKV infection. There remains a need for treatments that are effective to treat individuals who have CHIKV infection.